MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis

MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis Ning Wang, Xiaoyu Zhang, Yan Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9544748/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The transition from mitosis to meiosis represents a fundamental cell-fate decision that requires coordinated remodeling of transcriptional and metabolic programs. While key transcriptional regulators of meiotic entry have been defined, how metabolic flux directly governs this process remains unclear. Here, we identify a monocarboxylate transporter1 (MCT1)-dependent metabolic checkpoint that controls meiotic progression in mammalian spermatogenesis. Through integrative single-cell transcriptomics, metabolic profiling, and computational perturbation modeling, we show that Stra8-driven meiotic initiation is coupled to a metabolic switch favoring monocarboxylic acid metabolism, prominently involving MCT1 (encoded by Slc16a1). Germ cell–specific deletion of Slc16a1 results in a complete arrest at the pachytene stage, characterized by defective homologous recombination, persistent DNA damage, and failure to activate the meiotic transcriptional program. Multi-omic analyses reveal that loss of MCT1 induces a metabolic stress-like state, suppresses expression of key meiotic regulators, and disrupts progression through the pachytene checkpoint. Mechanistically, we demonstrate that MCT1-mediated lactate influx drives histone H4 lysine 12 lactylation (H4K12la) at promoters of meiotic genes, thereby epigenetically licensing their expression. In the absence of MCT1, H4K12la deposition is lost at meiotic loci and redistributed toward stress-response pathways. Together, our findings suggest MCT1-mediated metabolism as an instructive signal that integrates metabolic state with epigenetic regulation to govern meiotic cell-fate progression, defining a previously unrecognized metabolic checkpoint at pachytene. Biological sciences/Developmental biology/Germline development/Spermatogenesis Biological sciences/Cell biology/Chromosomes Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryFigures.pdf Supplementary Figures S1–S6 sourcedata.xlsx Source data Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9544748","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":631495107,"identity":"fc05ebbb-e1b7-44d3-9c9d-b3b2c4cf1f9c","order_by":0,"name":"Ning Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsUlEQVRIiWNgGAWjYNCCChsDCIONaC1n0kjVwth2mAQt5hLJzx5+YTtvbHDt8AOGD2WHCWuxnJFmbizDc9vM4HaaAeOMc0RoMbidYCYtIXHbxuB2DgMzbxtRWtK/SUsYnINo+UuclhwzyQ8JB8zAWhiJ0nL/TZk0w4FkY0mgXw72nEsnQsuZ49skf/6zM+y7nfzwwY8ya8JaQICZB8o4QJx6IGD8QbTSUTAKRsEoGJEAADCHO9tan4b0AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-4647-5880","institution":"University of Kansas Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Ning","middleName":"","lastName":"Wang","suffix":""},{"id":631495108,"identity":"8169301a-4eb6-4d12-b30d-f059bc340dd4","order_by":1,"name":"Xiaoyu Zhang","email":"","orcid":"","institution":"University of Kansas Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyu","middleName":"","lastName":"Zhang","suffix":""},{"id":631495109,"identity":"e37c47c0-a4b3-46b6-9f35-3cadf2d30693","order_by":2,"name":"Yan Liu","email":"","orcid":"","institution":"University of Kansas Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2026-04-27 17:10:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9544748/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9544748/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108182272,"identity":"42171f97-3146-4224-9f45-432fa9727cb6","added_by":"auto","created_at":"2026-04-30 08:59:17","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8747463,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ManuscriptMCT1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9544748/v1_covered_737b1e7e-1956-4cca-9247-19f58030d0ce.pdf"},{"id":108161824,"identity":"be2a5738-cbb1-47dc-9e5a-947eaa61390d","added_by":"auto","created_at":"2026-04-30 04:25:06","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":8932389,"visible":true,"origin":"","legend":"Supplementary Figures S1\u0026#x2013;S6","description":"","filename":"SupplementaryFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9544748/v1/832335dff693dd3251368031.pdf"},{"id":108161863,"identity":"46425317-8313-49d6-b97e-00680ad0679c","added_by":"auto","created_at":"2026-04-30 04:25:16","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":8212856,"visible":true,"origin":"","legend":"Source data","description":"","filename":"sourcedata.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-9544748/v1/6ffdad8e4198344f2d39dc09.xlsx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9544748/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9544748/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The transition from mitosis to meiosis represents a fundamental cell-fate decision that requires coordinated remodeling of transcriptional and metabolic programs. While key transcriptional regulators of meiotic entry have been defined, how metabolic flux directly governs this process remains unclear. Here, we identify a monocarboxylate transporter1 (MCT1)-dependent metabolic checkpoint that controls meiotic progression in mammalian spermatogenesis. Through integrative single-cell transcriptomics, metabolic profiling, and computational perturbation modeling, we show that Stra8-driven meiotic initiation is coupled to a metabolic switch favoring monocarboxylic acid metabolism, prominently involving MCT1 (encoded by Slc16a1). Germ cell–specific deletion of Slc16a1 results in a complete arrest at the pachytene stage, characterized by defective homologous recombination, persistent DNA damage, and failure to activate the meiotic transcriptional program. Multi-omic analyses reveal that loss of MCT1 induces a metabolic stress-like state, suppresses expression of key meiotic regulators, and disrupts progression through the pachytene checkpoint. Mechanistically, we demonstrate that MCT1-mediated lactate influx drives histone H4 lysine 12 lactylation (H4K12la) at promoters of meiotic genes, thereby epigenetically licensing their expression. In the absence of MCT1, H4K12la deposition is lost at meiotic loci and redistributed toward stress-response pathways. Together, our findings suggest MCT1-mediated metabolism as an instructive signal that integrates metabolic state with epigenetic regulation to govern meiotic cell-fate progression, defining a previously unrecognized metabolic checkpoint at pachytene.","manuscriptTitle":"MCT1 governs a metabolic checkpoint at pachytene during spermatogenesis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-30 04:24:55","doi":"10.21203/rs.3.rs-9544748/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"11db5b70-440f-4536-9a75-144f2752062f","owner":[],"postedDate":"April 30th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-12T04:33:39+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-06T18:47:24+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-06T03:04:08+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-05-04T14:45:18+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-04-30T10:37:58+00:00","index":1,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":67212940,"name":"Biological sciences/Developmental biology/Germline development/Spermatogenesis"},{"id":67212941,"name":"Biological sciences/Cell biology/Chromosomes"}],"tags":[],"updatedAt":"2026-04-30T04:24:55+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-30 04:24:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9544748","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9544748","identity":"rs-9544748","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}